PROJECT SUMMARY Individuals with Parkinson's disease (PD) not only have an accelerated decline in substantia nigra dopamine (SN-DA) neurons and locus coeruleus norepinephrine (LC-NA) neurons; they also have reduced SN brain-derived neurotrophic factor (BDNF) levels and increased oxidative stress. Preliminary studies from our laboratory show that chronic vagus nerve stimulation (VNS) retains the number of DAergic and NAergic neurons, improves locomotor activity, and increases BDNF in the brain. Preclinical studies have shown that VNS exerts its protective effects via brainstem nuclei, such as the LC. The use of vagus nerve stimulation (VNS) has already been implemented for the clinical use of treatment-resistant depression and epilepsy. To date, no studies have assessed the effects of VNS on PD pathology and motor dysfunction VNS models have shown increased NAergic levels and BDNF expression in LC target regions via PPAR? activation. In addition VNS has been shown to exert anti-oxidant effects in various peripheral and central nervous system models. Based on these findings we want to further explore the use of VNS as a treatment strategy for PD. In addition, we want to determine a potential mechanism by which VNS is exerting its neuroprotective effects, specifically, if VNS has anti-oxidant and neuroprotective signaling effects in a double lesion model of PD. Our overall hypothesis is that chronic vagus nerve stimulation will alleviate PD-like pathology and motor dysfunction as a result of combined DAergic/NAergic degeneration via PPAR? activation: 1) as an antioxidant to reduce oxidative stress and 2) as a transcription factor to increase BDNF expression. To address this hypothesis, two aims were formulated: Aim 1) Chronic vagus nerve stimulation attenuates motor impairment and DAergic/NAergic degeneration by reducing oxidative stress via PPAR? activation; and Aim 2) Chronic vagus nerve stimulation abrogates DAergic/NAergic degeneration by increasing BDNF expression and activation of the BDNF receptor, TrkB. Findings from these studies will provide insight into the mechanism by which VNS alleviates neuronal damage as a result of PD. Furthermore, these studies will provide information on novel treatment strategies, VNS and the systemic administration of PPAR? agonists, to be implemented in clinics for PD patients.